For some human diseases, including heart and liver failure, organ transplantation is the only alternative to certain death. While there were only 4,843 organ donors in the U.S. in 1993, there were 2,866 heart and 3,040 liver failure patients on the waiting list for these organs (UNOS Update, 10(2), 1994). Thus, because of timing and tissue matching problems, many patients die each year for lack of an available organ. For those lucky enough to receive an organ, the results are still less than ideal. The transplant procedure constitutes major surgery which is associated with attendant risks and is exceedingly expensive. After the surgery, the patient must be placed on a regimen of immunosuppressive drugs to keep the immune system from destroying the transplanted organ. As a consequence, the patient's entire immune system is suppressed for the rest of his life, significantly lowering his defenses against other serious disease threats such as infections, viruses or cancers.
For other diseases including kidney failure, pancreas failure and cystic fibrosis, transplantation has a lower mortality and morbidity rate than any alternative therapy. Even with its attendant problems of organ scarcity, surgical risk, high cost and permanent immunosuppression, for some of these cases it is still a more practical therapy than any alternative. The physician's choice in these cases is dependent on many variables including age, general health, severity of the condition, availability of organs and others factors. In 1994, there were 25,033 patients on the waiting list for human kidneys, 181 for pancreases and 1,250 for lungs (UNOS Update, 10:2, 1994).
For still other diseases, transplantation is known to be effective, although its attendant problems preclude its practical therapeutic use. This is true for many of the kidney, pancreas and lung patients described above. It is also true where whole pancreas transplantation can cure diabetes or liver transplantation can cure hemophilia but the risks outweigh the rewards.
Recently, for certain disease states, tissue transplants, as opposed to whole organ transplants, have been shown to be therapeutic in animals and even in man (Scharp et al., Transplantation, 51:76-85, 1991). Tissue transplantation requires full immunosuppression and carries the same risks and problems as already discussed for whole organ immunosuppression. The following treatments address the rejection of the transplanted tissue.
One implantation method involves pre-inoculation in the thymus with a small dose of cells, full temporary immunosuppression, then a full therapeutic dose at another site (Posselt et al., Annals of Surgery, 214:363-373, 1991). First, this has only been shown to work in rodents to date. No large animal or human test has been successful. Second, the human adult thymus is shrunken and may not be practical to treat with an adequate pre-dose. Third, the immunosuppression step, while temporary, does subject the patient to risks for that period of time. Fourth, it is not known whether a fully therapeutic dose will be tolerated, (i.e. not rejected) in humans. Fifth, this procedure may not protect against autoimmune destruction even if it does prevent rejection.
Another method of preventing rejection is irradiation of the recipient's bone marrow immune cells, implantation of bone marrow cells from the donor, then implantation of a full therapeutic dose of tissue or organ from the same donor (Illstad et al., J. Exp. Med., 174:467-478, 1991). First, this has not been shown to work for tissue transplants in humans. Second, irradiation of immune cells, either partial or whole body, carries serious risks. Third, it is not known if the immune system will adequately protect from other threats. Fourth, it is not known if the method will protect from both rejection and autoimmune destruction in those disease states.
A further method of treatment to prevent rejection is by using monoclonal antibodies to suppress certain parts of the immune system (Andersson et al., J. Autoimmun., 4:733-742, 1991). These tests have only been performed in rodents so it is not known if they would succeed in humans. Also, it is not known if the proper monoclonal antibody could be identified and created for each different disease state. In addition, the overall affect of these agents on the human immune system is not known.
Still another method of preventing rejection is encapsulation of the transplanted tissue in a semi-permeable membrane device which allows oxygen, nutrients and other small molecules to pass but prevents entry of large immune system cells (Lacy et al., Science, 254:1782-1784, 1991; Sullivan et al., Science, 252:718-721, 1991). There are several unresolved problems associated with this method. First, none of these devices has been shown to protect a therapeutic transplant in humans. To be suitable for human use, the material must be biocompatible; it must be sufficiently strong to last a long time when implanted; its porosity must be exactly correct to allow survival and function of the enclosed cells while keeping out cells and perhaps antibodies of the immune system; and finally, the device itself must be large enough to contain enough cells for a fully therapeutic implant and yet small enough to allow for some reasonable method of implantation which causes no damage to other internal organs.
To date, there has been very little effort to use transplantation as a potential prevention of disease due to all of the problems associated with transplantation as previously described. In addition, it is not yet known where transplantation can actually prevent a disease from occurring other than the obvious case of whole organ failures. Moreover, for many disease states, it is not known who will be afflicted. There is some evidence that interventional transplantation can have some preventive effect in rodents (Miller et al., J. Neurol. Immunol., 46:73-82, 1993; van Vollenhoven et al., Cell. Immunol., 115:146-155, 1988). Thus, a major role for preventive transplantation has not been investigated.